Correspondence

High-Dose Epinephrine in Cardiopulmonary Resuscitation

N Engl J Med 1993; 328:735-736March 11, 1993

Article

To the Editor:

The recent reports by Stiell1 and Brown2 and their colleagues (Oct. 8 issue) on the use of high-dose epinephrine for cardiac arrest in adults show an apparent lack of benefit. Stiell et al. found that some patients receiving high doses of epinephrine had a worse outcome, although Brown et al. found no adverse effects. These studies have as a theoretical basis studies in laboratory animals that had improved myocardial and cerebral blood flow when given epinephrine after cardiac arrest. However, other vascular beds, such as those of the mesentery and kidneys, are prone to the development of intense vasoconstriction in the setting of cardiac arrest and shock, and vasoconstrictors such as epinephrine may accentuate this process.

The infusion of vasoconstrictors has been demonstrated to produce acute renal failure in animals3,4. Stiell et al. and Brown et al., however, did not report data on renal function. We recently reviewed 420 consecutive cases of cardiac arrest at our institution and found a 28.6 percent incidence of acute renal failure among patients who survived for at least 24 hours after cardiac arrest5. Patients in whom acute renal failure developed were found to have received markedly larger doses of epinephrine during resuscitative efforts than patients without renal failure. It is also noteworthy that the patients with acute renal failure in our series had a dismal long-term survival rate, as compared with those without renal failure (6.3 percent vs. 47.5 percent, P<0.05). It would be interesting to know the incidence of acute renal failure in the groups given high doses of epinephrine,1,2 since this might be another factor that could account for the finding that certain patients receiving high-dose epinephrine had worse outcomes.

Joseph Mattana, M.D.
Pravin C. Singhal, M.D.
Long Island Jewish Medical Center, New Hyde Park, NY 11042

5 References

1. 1

   Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992;327:1045-1050
   Full Text | Web of Science | Medline

2. 2

   Brown CG, Martin DR, Pepe PE, et al. A comparison of standard-dose and high-dose epinephrine in cardiac arrest outside the hospital. N Engl J Med 1992;327:1051-1055
   Full Text | Web of Science | Medline

3. 3

   Mauk RH, Patak RV, Fadem SZ, Lifschitz MD, Stein JH. Effect of prostaglandin E administration in a nephrotoxic and a vasoconstrictor model of acute renal failure. Kidney Int 1977;12:122-130
   CrossRef | Web of Science | Medline

4. 4

   Patak RV, Fadem SZ, Lifschitz MD, Stein JH. Study of factors which modify the development of norepinephrine-induced acute renal failure in the dog. Kidney Int 1979;15:227-237
   CrossRef | Web of Science | Medline

5. 5

   Mattana J, Singhal PC. Acute renal failure following cardiopulmonary resuscitation. Clin Res 1992;40:251A-251A abstract.
   

To the Editor:

With regard to the article of Stiell et al. on high-dose epinephrine for cardiopulmonary resuscitation, in my view the usefulness of epinephrine is not theoretically explainable simply in terms of its activity as an arterial α-adrenergic-receptor stimulant1,2 inducing generalized vasoconstriction. There are at least two major reasons for questioning this explanation.

First, epinephrine has a preferential affinity for peripheral vascular β₂-receptors, which mediate vasodilatation, over α-receptors, which mediate constriction. This is in contrast to norepinephrine, which has little affinity for the β₂-receptors of the vasculature3. Consequently, low-dose epinephrine should dilate the skeletal-muscle vasculature (which makes up a major part of body mass) as well as the capacious splanchnic vasculature, both beds with large numbers of β-receptors. Only high-dose epinephrine would, after saturation of peripheral β₂-receptors, mediate widespread vasoconstriction.

Second, during ventricular fibrillation or asystole, and the resultant cerebral ischemia, the ischemic response of the central nervous system would be activated, causing massive discharge of the sympathetic axis, including release of norepinephrine from nerves and release of epinephrine from the adrenal medulla. This combined release of norepinephrine and epinephrine during the initial phases is generally regarded as sufficient for maximal vasoconstriction of the vasculature4,5. Consequently, the timing of the exogenous administration of additional epinephrine during resuscitation attempts is critical to interpretation.

With regard to coronary-artery dilation by epinephrine, the primacy of locally generated metabolites as coronary vasodilators in severely compromised myocardium is well known, and additional dilation is not likely. It appears that the mechanism of action of epinephrine therapy, if it is effective in resuscitation, has not yet been fully resolved.

Stanley Kalsner, Ph.D.
City University of New York Medical School, New York, NY 10031

5 References

1. 1

   Stiell IG, Hebert PC, Weitzman BN, et al. High-dose epinephrine in adult cardiac arrest. N Engl J Med 1992;327:1045-1050
   Full Text | Web of Science | Medline

2. 2

   Otto CW, Yakaitis RW, Blitt CD. Mechanism of action of epinephrine in resuscitation from asphyxial arrest. Crit Care Med 1981;9:364-365
   CrossRef | Web of Science | Medline

3. 3

   Lefkowitz RJ, Hoffman BB, Taylor P. Neurohumoral transmission: the autonomic and somatic motor nervous systems. In: Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:84-121.
   

4. 4

   Guyton AC. Textbook of medical physiology. 8th ed. Philadelphia: W.B. Saunders, 1991.
   

5. 5

   Kern KB, Elchisak MA, Sanders AB, Badylak SF, Tacker WA, Ewy GA. Plasma catecholamines and resuscitation from prolonged cardiac arrest. Crit Care Med 1989;17:786-791
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Drs. Mattana and Singhal have raised the question of a possible increased risk of acute renal failure in surviving patients who receive high doses of epinephrine during resuscitative efforts after cardiac arrest. In our experience, acute renal failure has not been a common complication after successful resuscitation of patients who have primary cardiac arrest in an out-of-hospital setting. Therefore, we did not specifically address the question of acute renal failure after resuscitation in our study. However, we did examine in-hospital mortality rates and days of hospitalization in both the group given the standard dose of epinephrine (0.5 to 2.0 mg) and the group given the high dose (5 to 20 mg) as an indirect measure of serious complications.

The percentages of patients admitted to the hospital who died before discharge were similar in the two groups (P = 0.98). In addition, the average number of days that the patients remained hospitalized after resuscitation was similar: 7.8 days in the standard-dose group and 8.0 days in the high-dose group (P = 0.91). If acute renal failure had been a common complication among patients given the high dose, one would assume that their hospitalization would have been protracted.

Several additional studies have addressed the issue of potential complications after the administration of epinephrine for cardiac arrest. Although the issue of acute renal failure was not addressed,1,2 these studies also failed to show significant differences in complication rates between patients given standard doses and those given high doses. Furthermore, a study of at least one case series failed to demonstrate the development of acute renal failure after the use of high doses of epinephrine for cardiac arrest3.

The suggestion of Drs. Mattana and Singhal that the acute renal failure observed in their study4 was caused by a slightly higher dose of epinephrine deserves further scrutiny. In their study, the larger dose given the group with renal failure was associated with a longer duration of cardiopulmonary resuscitation (12.0 minutes, vs. 6.7 minutes in the group without renal failure). Therefore, it is more likely that the increased dose of epinephrine received by the patients with post-resuscitation acute renal failure is actually a marker for more prolonged efforts at resuscitation, and that therefore the higher rate of renal failure was not a direct effect of the drug. In addition, the group with renal failure had a significantly greater percentage of patients with renal insufficiency before cardiac arrest4.

Charles G. Brown, M.D.
Daniel R. Martin, M.D.
Ohio State University, Columbus, OH 43210

Paul E. Pepe, M.D.
Baylor College of Medicine, Houston, TX 77030

4 References

1. 1

   Callaham M, Barton CW, Kayser S. Potential complications of high-dose epinephrine therapy in patients resuscitated from cardiac arrest. JAMA 1991;265:1117-1122
   CrossRef | Web of Science | Medline

2. 2

   Callaham M, Madsen CD, Barton CW, Saunders CE, Pointer J. A randomized clinical trial of high-dose epinephrine and norepinephrine vs standard-dose epinephrine in prehospital cardiac arrest. JAMA 1992;268:2667-2672
   CrossRef | Web of Science | Medline

3. 3

   Martin D, Werman HA, Brown CG. Four case studies: high-dose epinephrine in cardiac arrest. Ann Emerg Med 1990;19:322-326
   CrossRef | Web of Science | Medline

4. 4

   Mattana J, Singhal PC. Acute renal failure following cardiopulmonary resuscitation. Clin Res 1992;40:251A-251A abstract.